Previous research has implicated the mesotelencephalic dopaminergic system as the primary substrate mediating the reinforcing effects of many abused drugs. However, endogenous opioid peptides have also been implicated in this phenomenon. The presence of enkephalins in the nucleus accumbens-pallidal projection, and the demonstrated importance of this pathway in reinforcement, provides an anatomical basis for such a hypothesis. Previously, using microdialysis linked to a solid-phase radioimmunoassay, we demonstrated that opiate administration elevates extracellular concentrations of enkephalins in the pallidum. The first part of the current proposal will examine further the mechanisms underlying this effect. Repeated intermittent administration of opiate and psychostimulant drugs induces a state of behavioral sensitization believed to be largely dependent on a sensitized mesotelencephalic dopamine system. This phenomenon has been implicated in the attribution of 'incentive salience' to environmental cues associated with drug administration. However, not all the evidence is in favor of such a hypothesis and the possible role of other neurotransmitters/neuromodulators in this process needs to be investigated. Our preliminary data suggest that heroin-induced pallidal enkephalin release may exhibit acute sensitization. We will therefore examine if repeated intermittent administration of heroin induces sensitization to the enkephalin-releasing effect of this drug. We will determine for how long such sensitization persists and whether its expression is dependent on conditioned environmental cues. The final part of the proposal will combine microdialysis with a modified conditioned place-preference paradigm to examine if environmental cues themselves elicit a pallidal enkephalin release response in animals conditioned to associate such cues with heroin administration. These studies will provide valuable information concerning the mechanisms underlying heroin addiction.